The effect of baicalein on endoplasmic reticulum stress and autophagy on liver damage

Üstüner, Mehmet Cengiz; Tanrıkut, Cihan; Üstüner, Derya; Kolaç, Umut Kerem; Köroğlu, Zeynep Özdemir; Burukoğlu, Dilek; Entok, Emre

doi:10.1177/09603271211003634

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…It has also been published that ER stress invokes liver fibrosis primarily due to ER stress within HSCs due to their activation ( Koo et al, 2016 ). Since hepatocytes are known to be sensitive to CCl 4 -mediated ER stress ( Üstüner et al, 2021 ), we examined whether crosstalk between activated HSCs and hepatocytes in a co-culture system promoted the ER stress response in hepatocytes and whether AKAP12 regulated this crosstalk. Modulating HSC activation through AKAP12 regulated the ER stress response in hepatocytes in culture.…”

Section: Discussionmentioning

confidence: 99%

Targeting A-kinase anchoring protein 12 phosphorylation in hepatic stellate cells regulates liver injury and fibrosis in mouse models

Ramani

Mavila

Abeynayake

et al. 2022

eLife

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Trans-differentiation of hepatic stellate cells (HSCs) to activated state potentiates liver fibrosis through release of extracellular matrix (ECM) components, distorting the liver architecture. Since limited antifibrotics are available, pharmacological intervention targeting activated HSCs may be considered for therapy. A-kinase anchoring protein 12 (AKAP12) is a scaffolding protein that directs protein kinases A/C (PKA/PKC) and cyclins to specific locations spatiotemporally controlling their biological effects. It has been shown that AKAP12’s scaffolding functions are altered by phosphorylation. In previously published work, observed an association between AKAP12 phosphorylation and HSC activation. In this work, we demonstrate that AKAP12’s scaffolding activity toward the endoplasmic reticulum (ER)-resident collagen chaperone, heat-shock protein 47 (HSP47) is strongly inhibited by AKAP12’s site-specific phosphorylation in activated HSCs. CRISPR-directed gene editing of AKAP12’s phospho-sites restores its scaffolding toward HSP47, inhibiting HSP47’s collagen maturation functions, and HSC activation. AKAP12 phospho-editing dramatically inhibits fibrosis, ER stress response, HSC inflammatory signaling, and liver injury in mice. Our overall findings suggest a pro-fibrogenic role of AKAP12 phosphorylation that may be targeted for therapeutic intervention in liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Targeting A-kinase anchoring protein 12 phosphorylation in hepatic stellate cells regulates liver injury and fibrosis in mouse models

Ramani

Mavila

Abeynayake

et al. 2022

eLife

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“…An increasing number of studies have suggested that baicalein may regulate autophagy in liver cancer cells to promote apoptosis and enhance chemosensitivity [ 44 , 47 ]. In addition, baicalein has also been shown to protect liver cells from damage through autophagy [ 38 , 48 ]. However, how baicalein regulates hepatic autophagy is still unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have noted that baicalein represses the phosphorylation of mTOR and activates ULK1 signaling [ 79 , 80 ], suggesting that baicalein may activate hepatic autophagy by suppressing the activation of mTOR and/or ULK phosphorylation. Moreover, a recent study showed that baicalein triggered ER stress to protect the liver from CCl 4 -induced damage [ 48 ]. In accordance with these findings, whether ER stress and downstream unfolded protein response (UPR) signaling can trigger the initiation of baicalein-induced autophagy by transcriptionally controlling ATG gene expression in liver cells can be examined.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to its role in promoting autophagy, baicalein has been shown to suppress autophagy by targeting guanosine triphosphatase (GTPase) and thus enhance HCC cell chemosensitivity [ 47 ]. Moreover, baicalein has been reported to protect the liver from carbon tetrachloride (CCl 4 )- and acetaminophen (APAP)-induced liver injury by altering autophagy [ 38 , 48 ]. Collectively, these studies have implicated baicalein in differentially exerted hepatotoxicity and anti-HCC processes through its modulation of hepatic autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN

Chang

Hsiao

2022

Cells

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The elimination of intracellular components by autophagy maintains metabolic homeostasis and is a quality-control pathway that enables organelle regeneration. Mitophagy is a type of selective autophagy that regulates mitochondrial turnover, and the dysregulation of mitophagy has been implicated in the pathogenesis of liver diseases. However, the detailed molecular mechanism underlying mitophagy regulation in liver cells remains unclear, and the small molecules that may potentially modulate hepatic mitophagy are still unavailable. Here, we report that baicalein, a flavonoid extracted from Scutellaria baicalensis, induces the entire autophagy that proceeds through the autolysosome maturation stage in human hepatoma cells. In addition, baicalein-induced autophagy is demonstrated to target mitochondria for degradation. Further studies show that baicalein triggers the translocation of Parkin and TBK1 to mitochondria to induce mitophagy. Moreover, the phosphorylation of TBK1 at Ser172 and ubiquitin at Ser65 is shown to trigger mitophagy in baicalein-treated cells. Furthermore, two specific autophagy cargo receptors, NDP52 and OPTN, that function in baicalein-activated mitophagy are identified. Taken together, these findings not only delineate the molecular process of Parkin-dependent mitophagy in liver cells, but also reveal baicalein as a novel inducer of hepatic mitophagy.

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“…It has also been published that ER stress invokes liver fibrosis primarily due to ER stress within HSCs due to their activation (36). Since hepatocytes are known to be sensitive to CCl4-mediated ER stress (52), we examined whether crosstalk between activated HSCs and hepatocytes in a co-culture system promoted the ER stress response in hepatocytes and whether AKAP12 regulated this crosstalk. Modulating HSC activation through AKAP12 regulated the ER stress response in hepatocytes in culture.…”

Section: Discussionmentioning

confidence: 99%

Targeting A-Kinase Anchoring Protein 12 Phosphorylation in Hepatic Stellate Cells Regulates Liver Injury and Fibrosis in Mouse Models

Ramani

Mavila

Abeynayake

et al. 2022

Preprint

View full text Add to dashboard Cite

Trans-differentiation of hepatic stellate cells (HSCs) to activated state potentiates liver fibrosis through release of extracellular matrix (ECM) components, distorting the liver architecture. Since limited antifibrotics are available, pharmacological intervention targeting activated HSCs may be considered for therapy. A-kinase anchoring protein 12 (AKAP12) is a scaffolding protein that directs protein kinases A/C (PKA/PKC) and cyclins to specific locations spatiotemporally controlling their biological effects. It has been shown that AKAP12’s scaffolding functions are altered by phosphorylation. In previously published work, observed an association between AKAP12 phosphorylation and HSC activation. In this work we demonstrate that AKAP12’s scaffolding activity towards the endoplasmic reticulum (ER)-resident collagen chaperone, heat-shock protein 47 (HSP47) is strongly inhibited by AKAP12’s site-specific phosphorylation in activated HSCs. CRISPR-directed gene editing of AKAP12’s phosphosites restores its scaffolding towards HSP47, inhibiting HSP47’s collagen maturation functions and HSC activation. AKAP12 phospho-editing dramatically inhibits fibrosis, ER stress response, HSC inflammatory signaling and liver injury in mice. Our overall findings suggest a pro-fibrogenic role of AKAP12 phosphorylation that may be targeted for therapeutic intervention in liver fibrosis.

show abstract

The effect of baicalein on endoplasmic reticulum stress and autophagy on liver damage

Cited by 11 publications

References 42 publications

Targeting A-kinase anchoring protein 12 phosphorylation in hepatic stellate cells regulates liver injury and fibrosis in mouse models

Targeting A-kinase anchoring protein 12 phosphorylation in hepatic stellate cells regulates liver injury and fibrosis in mouse models

Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN

Targeting A-Kinase Anchoring Protein 12 Phosphorylation in Hepatic Stellate Cells Regulates Liver Injury and Fibrosis in Mouse Models

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